Introduction to Microbial
Pathogenesis
Infectious Agent
(Proposed by Henle in 1840; demonstrated by Koch in 1876)
• “a single [type] of micro-organism could be
isolated from all animals suffering from anthrax;
• the disease could be reproduced in an
experimental host by infection with a pure
culture of this bacterium; and
• the same [type] of micro-organism could
subsequently be reisolated from the
experimental host.”
Infectious Agents in Humans
•
•
•
•
•
•
Prion - scrapie
Viruses – HIV, influenza
Bacteria – Mycobacterium tuberculosis
Fungi – Candida albicans
Protozoa – Plasmodium falciparum
Helminths – Schistosoma mansoni
Prion
normal
abnormal
Virus
Bacteria
Fungi
Protozoa
Helminths
Ascaris lumbricoides : human intestinal roundworm
Barriers
Physical barrier: Skin, Mucosal gel overlaying
epithelium (respiratory, gastrointestinal, urogenitary)
Microbiological barrier: Normal microbioflora
Initiation of Disease
Initiation of Disease
contact with pathogenic organism:
human to human, animal to human
Transmission
• Aerosols to respiratory mucosa
• Fomite to nasopharyngial or conjungtive
mucosa
• Fecal – Oral Route
• Mucosal surface to mucosal surface
Infectious Disease Cycle
Transmission
Dissemination
Breach of epithelium
or
Colonization of mucosa
Evasion of
host defense
Multiplication
Attachment to target cells
Invasion
to subepithelial or intracellular space
Adherence/Attachment
Specific Adherence
• Receptor-mediated adhesion
Non-specific Adherence
• Hydrophobic/lipophilic-
mediated adhesion
•Hydrophobic struture on
microbial cell envelope
•Lipophilic area on host cell
membrane
Specific Adherence
Microbial adhesin
Host cell receptor
Bacterial
Fimbrial
Uropahogenic E coli
P-pili
Afimbrial
Staphylococcus aureus
fibronectin binding protein
Herpes simplex 1 virus
glycoproteins B, C and D
Viral
Measles virus
hemagglutinin (H) protein
Epithelial cell
glycolipid receptor globobiose
Epithelial, endothelial, fibroblastic cells
fibronectin receptor integrin
Epithelial cells of skin and mucosa
heparin sulfate
Epithelial, endothelial cells, mononcytesmacrophages (and others)
CD46
Invasion
bacterial
•Transcytosis across superficial
epithelium to subepithilial space
•Induce engulfment by nonphagocytic host cells
•Local reararrangement of host
cell cytoskeleton
viral
•Pass through plasma membrane
•Membrane invagination
•Clathrin
•Fusion with host cell plasma
membrane
•Phagocytosis
•HIV gp120/41
•Utilization of membranous cell
gateway
•T lymphocyte CD4
•Macrophage CCR5
Evasion/Manipulation of Host Defense
• Modulation of innate/inflammatory response
• Resistance to phagocytic killing in subepithelial space
• Serum resistance
• Antigenic variation
Modulation of Innate/Inflammatory Response
Adhesin-directed degranulation of mast cells
histamine
cytokines
degranulation
mast cell
E. coli bound to mouse mast cell
proteoglycans
Resistance to phagocytic killing in subepithelial space
• Inhibit phagocyte mobilization :(chemotaxis, complement activation)
Inhibit chemoattractants: Streptococcus pyogenes degrades C5a
Inhibit chemotaxis: Pertussis toxin causes intracellular rise in cAMP in
neutrophils to impair chemotaxis
• Avoid ingestion
kill phagocytes: Streptolysin O lyses PMNs; Staphylococcus
aureus alpha, beta and gamma toxins and leucocidin lyses
PMNs
capsular protection from opsonization: M proteins,
Streptococcus pyogenes
Bacterial capsules that resemble self: Neisseria meningitidis
(sialic acid); Streptococcus pyogenes (hyaluronic acid)
• Survive within phagocyte
Survival within phagocyte
Escape endosome or phagolysosome:
- Shigella, Listeria monocytogenes
Inhibit phagosome-lysosome fusion
- Legionella pneumophila, Mycobacterium tuberculosis, Salmonella
Survive within phagolysosome (resist enzymatic degration
or neutralize toxic products)
- Inactivate reactive oxygen species: Salmonella, via superoxide
dismutase, catalase, recA
- Resist antimicrobial peptides: Host cationic peptides complexed with
SapA peptide
covalent binding
of activated sialic
acid
LPS galactose
residue
changes to
carbohydrate
portion of lipooligosaccharide
complement
resistance
Serum
Resistance
intracellular
lifestyle
prevent insertion
of C9 complex
into outer
membrane
N. gonorrhoeae
long O-side chains
of LPS
outer membrane
protein Rck
Salmonella
inhibit deposition
of C3
incorporate host
plasma proteins
(decay accelerating
factors) into
membrane
Schistosoma
mansoni
prevent C3
convertase
formation
sialic acid in LPS O
antigen
hydrolyzing
enzymes
inhabit blood cells
to avoid exposure
to humoral
factors
(e.g.complement)
PMN cells
lymphocytes
macrophages
red blood cells
Staphylococci
HIV
Mt
Plasmodiumium
Antigenic variation
Phase variation
Genetic variation
Transmission of genetic information via
mobile genetic elements
Gene recombination
VSG in Trypanosoma brucei
- Pili genes: Neisseria gonorrhoeae
Gene reassortment
- Influenza viruses A, B, C
High mutation rate
- RNA virus: Influenza viruses A, B, C
Recombination of replication products
- DNA virus: terminal redundancy in
linear genome
Cell and Tissue Damage
• Induction of apoptosis and necrosis
• Virus-induced cytopathic effect
• Induction of damaging host immune response
Induction of apoptosis
Phase variation
Genetic variation
Transmission of genetic information via
mobile genetic elements
Gene recombination
VSG in Trypanosoma brucei
- Pili genes: Neisseria gonorrhoeae
Gene reassortment
- Influenza viruses A, B, C
High mutation rate
- RNA virus: Influenza viruses A, B, C
Recombination of replication products
- DNA virus: terminal redundancy in
linear genome
Induction of Cell Death
Induction of apoptosis
Induction of necrosis
Virus-induced apoptosis:
HIV (CD4+ T cell), EBV, adenoviris
Bacterial toxins:
Interfere with cellular regulation of cAMP
Diptheria A-B toxin
-Bordetella pertussis (macrophage)
Activation of caspase-1
Salmonella (macrophages, DC)
SipB binds and activates caspase-1
Sigella flexneri (macrophages)
Invasion Plasmid antigen B (IpaB)
binds and activates host caspase-1
Virus-Induced Cytopathic Effect: Part 1
accumulation of reactive
oxygen intermediates
Cell lysis
accumulation of nitrogen
intermediates
accumulation of intracellular
calcium
Syncytia
formation
macrophages
viruses
Rotavirus,
cytomegalovirus, HIV
Paramyxoviruses
(respiratory syncytial
virus, parainfluenza
viruses, measels virus,
herpesvirus, some
retroviruses)
viral-encoded
fusion proteins
Virus-Induced Cytopathic Effect: Part 2
production of
eosinophilic or
basophilic
inclusion
bodies
viruses
Burkitt's
lymphoma
(EBV)
host cell
transformation
inactivation of p53 and Rb,
chromosomal destabilization,
enhancement of foreign DNA
integration and mutagenecity
DNA viruses
retroviruses
cervical
carcinoma
(human
papilloma
viruses)
adult T-cell
leukemia
(human T-cell
lymphotropic
virus type 1)
Induction of Damaging Host Immune Response
cross-reactivity between self
and mycobacterial heat shock
proteins
autoimmune
response
cross-reactivity between
components of endocardium
and joint synovial membrane
molecules and antigens in the
streptococcus cell wall
Acute rheumatic
fever after group A
streptococcal
pharyngitis
hypersensitivity
reactions
granuloma
formation
septic
shock/sepsis
toxic shock
Mycobacterium
tuberculosis
bacteria
LPS, peptidoglycan,
lipoteichoic acid,
toxins acting as
superantigens